研究者詳細 - 豊國　伸哉

論文 - 豊國　伸哉

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Amelioration of cisplatin toxicity by a fermented grain food product. 査読有り国際誌

Yukiko Minamiyama, Shigekazu Takemura, Shinya Toyokuni, Yoshihiro Nishino, Keiichi Yamasaki, Seikan Hai, Satoshi Yamamoto, Shigeru Okada

BioFactors (Oxford, England) 16 巻 ( 3-4 ) 頁： 105 - 15 2002年

記述言語：英語掲載種別：研究論文（学術雑誌）

The most noticeable hypothesis regarding the pathogenesis of cisplatin toxicity, seen mainly in kidney and intestine, is oxidative stress, an imbalance between free-radical generating cisplatin and radical scavenging systems. This paper describes the role of the antioxidant system in cisplatin-induced toxicity and the protective effect by a processed grain food (Antioxidant Biofactor: AOB), which has been shown to exhibit strong antioxidant activity. Male Fischer 344 rats were used. They were pre-fed either a basal diet (control, 15 g/day) or the diet supplemented with AOB to provide 6.5% or 20% of total diet throughout the experiment. Cisplatin (5 mg/kg, i.v.) was administered at the start of the experiment, and the animals were sacrificed 5 days later. Blood urea nitrogen (BUN) and plasma creatinine, NO2(-) and NO3(-) (NOx) were determined from the plasma. The levels of 4-hydroxy-2-nonenal (a lipid peroxidation product), 8-hydroxy-deoxyguanosine (8-OHdG, an oxidatively modified DNA adduct) and nitrotyrosine were histologically analyzed. The cisplatin administration resulted in a loss of body weight and elevations of BUN, serum creatinine and NOx levels, whereas AOB supplement reversed these effects. The severe morphological damages induced in the kidney and intestine by the cisplatin administration were markedly improved in the AOB group. The levels of lipid peroxidation, 8-OHdG, and nitrotyrosine all paralleled the morphological damage. The AOB effect was dose dependent. In conclusion, the present study suggests that certain food additives like AOB may be of benefit against the side effects of cisplatin.

DOI： 10.1002/biof.5520160306

PubMed

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酸化ストレス発がんの分子機構とその標的遺伝子 Open Access

豊國伸哉

環境変異原研究 23 巻 ( 3 ) 頁： 177 - 182 2001年12月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：日本環境変異原学会

Oxidative stress has been associated with carcinogenesis. In 1982, our laboratory established an oxys-tress-induced carcinogenesis model of rodent kidney by the use of an iron chelate, ferric nitrilotriacetate. This model is unique in that 1) only carcinoma, not sarcoma, is induced, 2) the induced tumor is of high malignant potential to kill the animal by pulmonary metastasis, peritoneal invasion or rupture of the primary tumor, and, 3) increase in a variety of covalently modified products including 8-oxoguanine, thymine-tyrosine cross-link, 4-hydroxy-2-nonenal and its modified proteins are demonstrated in its early stage. Since in general free radicals are not considered to react with specific target molecules in contrast with immune reaction, we undertook to answer the question whether there is any specific target gene (s) in this carcinogenesis model. By genetically analyzing F_1 hybrid rats, we found two chromosomal areas that showed a high incidence of loss of heterozygosity, which lead to a finding that p15^<INK4B>/p16^<INK4A> tumor suppressor genes are one of the major pathways responsible for this oxystress-induced cancer. Furthermore, by screening 84,000 transcripts by differential display techniques, we found that at least 15 genes associated with stress-response or cellular proliferation are differentially expressed in this model. We believe that not only genetic changes but also epigenetic changes play a role in oxidative stress-induced carcinogenesis.

Open Access

CiNii Research

酸化ストレス発がんの分子機構とその標的遺伝子 Open Access

豊國伸哉

環境変異原研究 23 巻 ( 3 ) 頁： 177 - 182 2001年12月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：日本環境変異原学会

Open Access

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Activation of lectin-like oxidized low-density lipoprotein receptor-1 induces apoptosis in cultured neonatal rat cardiac myocytes

Iwai-Kanai E., Hasegawa K., Sawamura T., Fujita M., Yanazume T., Toyokuni S., Adachi S., Kihara Y., Sasayama S.

Circulation 104 巻 ( 24 ) 頁： 2948 - 2954 2001年12月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Circulation

Background - Lectin-like oxidized LDL receptor-1 (LOX-1) was originally identified as a receptor expressed predominantly in endothelial cells. LOX-1 can also be expressed in other cell types, and the activation of the LOX-1 pathway has been implicated in apoptosis. There have been no reports, however, about LOX-1 expression in cardiac myocytes or regulation of myocardial cell apoptosis by LOX-1. Methods and Results - In primary cardiac myocytes from neonatal rats, immunohistochemical analyses using a specific monoclonal antibody against LOX-1 demonstrated that LOX-1 expression was markedly induced by stimulation with norepinephrine and endothelin-1. LOX-1 expression was upregulated in cardiac myocytes as well as in vessel walls of failing rat hearts in vivo. In the presence of a low concentration of oxidized LDL that did not induce apoptosis by itself, artificial overexpression of LOX-1 in cardiac myocytes in culture resulted in apoptosis. LOX-1 overexpression induced activation of p38 mitogen-activated protein kinase (MAPK) and oxidative stress in cardiac myocytes, as demonstrated by an increase in positive immunostaining for 8-hydroxy-2′-deoxyguanosine. Inhibition of p38 MAPK by cotransfection of a dominant-negative form of MKK6 as well as by administration of a specific inhibitor, SB203580 or FR167653, almost completely blocked the induction of apoptosis by LOX-1 activation. Antioxidant catalase also blocked LOX-1-induced apoptosis as well as activation of p38 MAPK. Conclusions - These findings demonstrate that LOX-1 expression in cardiac myocytes is induced by neurohormonal factors activated in heart failure and that LOX-1-dependent apoptosis in these cells requires p38 MAPK, a component of oxidant stress-sensitive signaling pathways.

DOI： 10.1161/hc4901.100381

Scopus

Activation of lectin-like oxidized low-density lipoprotein receptor-1 induces apoptosis in cultured neonatal rat cardiac myocytes

Iwai-Kanai E, Hasegawa K, Sawamura T, Fujita M, Yanazume T, Toyokuni S, Adachi S, Kihara Y, Sasayama S

CIRCULATION 104 巻 ( 24 ) 頁： 2948 - 2954 2001年12月

Activation of lectin-like oxidized low-density lipoprotein receptor-1 induces apoptosis in cultured neonatal rat cardiac myocytes 査読有り

Iwai-Kanai E, Hasegawa K, Sawamura T, Fujita M, Araki M, Yanazume T, Toyokuni S, Adachi S, Kihara Y, Sasayama S

Circulation 104 巻 ( 24 ) 頁： 2948 - 2954 2001年12月

境界悪性卵巣粘液性腫瘍の再発との細胞学的鑑別が困難であった子宮頸部上皮内腺癌の1例

小椋聖子, 清水恵子, 小林八郎, 豊國伸哉, 桜井幹己

日本臨床細胞学会雑誌 40 巻 ( 6 ) 頁： 636 - 640 2001年11月

境界悪性卵巣粘液性腫瘍の再発との細胞学的鑑別が困難であった子宮頸部上皮内腺癌の1例

小椋聖子, 清水恵子, 小林八郎, 豊國伸哉, 桜井幹己

日本臨床細胞学会雑誌 40 巻 ( 6 ) 頁： 636 - 640 2001年11月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：特定非営利活動法人日本臨床細胞学会

55歳,1経妊1経産.卵巣粘液性腫瘍の再発との鑑別が困難であった子宮頸部上皮内腺癌の1例を経験した.3年前に右卵巣腫瘍破裂で右付属器摘出術が施行され,右卵巣境界悪性粘液性腫瘍,腸上皮型,Ic期と診断され,外来経過観察中であった.子宮頸部擦過細胞診で異型腺細胞集団が認められ,子宮頸部腺系病変あるいは卵巣粘液性腫瘍の再発が疑われ,単純子宮全摘術と左付属器摘出術を施行した.摘出標本の組織診で子宮頸部上皮内腺癌と診断され,子宮体部,左付属器に悪性所見は認められなかった.婦人科領域の重複癌の診断では,細胞所見のみならず臨床所見や画像診断を加味した総合的判断が必要と思われた

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A novel selectin blocker alleviates oxidative stress of lung reperfusion injury. 国際誌 Open Access

Yoshimura T, Kawashima M, Nakamura T, Isowa N, Bando T, Hasegawa S, Kondo H, Toyokuni S, Wada H

The Journal of surgical research 101 巻 ( 1 ) 頁： 91 - 8 2001年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Surgical Research

Background. The importance of reactive oxygen species released through interaction of leukocyte/endothelial cell in ischemia-reperfusion injury of the lung is not yet fully understood. A novel selectin blocker, OJ-R9188, which inhibits the interaction, may alleviate oxidative stress and pulmonary dysfunction after warm ischemia-reperfusion. Materials and methods. Rat lungs were reperfused at 37°C for 60 min with an ex vivo model and were divided into three groups (n = 10). In the fresh group, lungs were reperfused immediately after harvest. In the OJ-R (-) and OJ-R (+) groups, lungs were reperfused after warm ischemia at 37°C for 90 min. In the OJ-R (+) group, rats received 100 μg per body of OJ-R9188 intravenously 10 min before the harvest. The electron spin resonance method was used to assess the direct scavenging activity of OJ-R9188. Results. Both shunt fractions and wet/dry weight ratios of the lung tissue after reperfusion in the OJ-R (+) group were significantly lower than those in the OJ-R (-) group. Oxidative DNA damage in the alveolar wall of the OJ-R (+) group, assessed by immunohistochemical quantitation of 8-hydroxy-2′-deoxyguanosine, was significantly lower than that of the OJ-R (-) group. Immunostaining of 3-nitro-L-tyrosine, which represents nitric oxide-mediated oxidative damage, was also more intense in the OJ-R (-) group than in the OJ-R (+) group. Direct scavenging activity of OJ-R9188 was not observed, and the number of leukocytes infiltrated to the lung tissue as seen by myeloperoxidase activity was not different between the OJ-R (-) and OJ-R (+) groups. Conclusions. A novel selectin blocker, OJ-R9188, improves pulmonary function after warm ischemia-reperfusion and alleviates reperfusion-induced oxidative alveolar damage. © 2001 Academic Press.

DOI： 10.1006/jsre.2001.6258

Characterization of a vitamin D receptor knockout mouse as a model of colorectal hyperproliferation and DNA damage

Kallay E, Pietschmann P, Toyokuni S, Bajna E, Hahn P, Mazzucco K, Bieglmayer C, Kato S, Cross HS

CARCINOGENESIS 22 巻 ( 9 ) 頁： 1429 - 1435 2001年9月

Characterization of a vitamin D receptor knockout mouse as a model of colorectal hyperproliferation and DNA damage

Kallay E, Pietschmann P, Toyokuni S, Bajna E, Hahn P, Mazzucco K, Bieglmayer C, Kato S, Cross HS

CARCINOGENESIS 22 巻 ( 9 ) 頁： 1429 - 1435 2001年9月

Curcumin and especially tetrahydrocurcumin ameliorate oxidative stress-induced renal injury in mice 査読有り国際誌

Okada K, Wangpoengtrakul C, Tanaka T, Toyokuni S, Uchida K, Osawa T

JOURNAL OF NUTRITION 131 巻 ( 8 ) 頁： 2090 - 2095 2001年8月

Curcumin and especially tetrahydrocurcumin ameliorate oxidative stress-induced renal injury in mice 査読有り国際誌

Okada K, Wangpoengtrakul C, Tanaka T, Toyokuni S, Uchida K, Osawa T

JOURNAL OF NUTRITION 131 巻 ( 8 ) 頁： 2090 - 2095 2001年8月

Role of Helicobacter pylori infection in gastroduodenal injury and gastric prostaglandin synthesis during long term/low dose aspirin therapy: A prospective placebo-controlled, double-blind randomized trial 査読有り国際誌

Pignatelli B., Bancel B., Plummer M., Toyokuni S., Patricot L., Ohshima H.

American Journal of Gastroenterology 96 巻 ( 6 ) 頁： 1751 - 1757 2001年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：American Journal of Gastroenterology

OBJECTIVES: Whether gastric infection with Helicobacter pylori increases the risk of gastric mucosal injury during long term/low dose aspirin therapy is unknown. We examined whether H. pylori infection enhances upper GI mucosal damage, assessed endoscopically, in volunteers given low dose aspirin. We studied 61 healthy men and women, 29 with and 32 without active H. pylori infection. METHODS: We treated volunteers for 45 days with a placebo or aspirin (either 81 mg every day or 325 mg every 3 days). Gastroduodenal mucosal damage was then assessed by endoscopy, as was gastric histology and ex vivo gastric mucosal prostaglandin E2 and F2α synthesis rates. RESULTS: Erosive disease from low dose aspirin (erosions and/or ulcers) occurred in 50% of H. pylori-infected volunteers and in 16% of their noninfected counterparts (p = 0.02). Aspirin caused a significantly higher average mucosal injury score in the gastric antrum in H. pylori-infected participants than in noninfected subjects (p = 0.03), and two H. pylori-infected subjects developed antral gastric ulcers. Subjects with H. pylori gastritis treated with the placebo had nearly 50% higher gastric mucosal prostaglandin (E2 plus F2α) synthesis rates than their noninfected counterparts (108 ± 6 ng/g/min versus 75 ± 6 ng/g/min, p < 0.001). Aspirin reduced mucosal prostaglandin synthesis to similar levels in infected and noninfected participants. CONCLUSIONS: Long term/low dose aspirin therapy led to more gastric mucosal damage when H. pylori gastritis was present than when it was absent, despite similar degrees of gastric mucosal prostaglandin depletion. © 2001 by Am. Coll. of Gastroenterology.

DOI： 10.1016/S0002-9270(01)02491-1

Scopus

Oxidative DNA damage in cultured cells and rat lungs by carcinogenic nickel compounds

Kawanishi S, Inoue S, Oikawa S, Yamashita N, Toyokuni S, Kawanishi M, Nishino K

FREE RADICAL BIOLOGY AND MEDICINE 31 巻 ( 1 ) 頁： 108 - 116 2001年7月

Oxidative DNA damage in cultured cells and rat lungs by carcinogenic nickel compounds

Kawanishi S., Inoue S., Oikawa S., Yamashita N., Toyokuni S., Kawanishi M., Nishino K.

Free Radical Biology and Medicine 31 巻 ( 1 ) 頁： 108 - 116 2001年7月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Free Radical Biology and Medicine

DNA damage in cultured cells and in lungs of rats induced by nickel compounds was investigated to clarify the mechanism of nickel carcinogenesis. DNA strand breaks in cultured cells exposed to nickel compounds were measured by using a pulsed field gel electrophoresis technique. Among nickel compounds (Ni3S2, NiO (black), NiO (green), and NiSO4), only Ni3S2, which is highly carcinogenic, induced lesions of both double- and single-stranded DNA in cultured human cells (Raji and HeLa cells). Treatment of cultured HeLa cells with Ni3S2 (10 μg/ml) induced a 1.5-fold increase in 8-hydroxy-2′-deoxyguanosine (8-OH-dG) compared with control, whereas NiO (black), NiO (green), and NiSO4 did not enhance the generation of 8-OH-dG. Intratracheal instillation of Ni3S2, NiO(black), and NiO(green) to Wistar rats increased 8-OH-dG in the lungs significantly. NiSO4 induced a smaller but significant increase in 8-OH-dG. Histological studies showed that all the nickel compounds used induced inflammation in lungs of the rats. Nitric oxide (NO) generation in phagocytic cells induced by Ni3S2, NiO(black), and NiO(green) was examined using macrophage cell line RAW 264.7 cells. NO generation in RAW 264.7 cells stimulated with lipopolysaccharide was enhanced by all nickel particles. Two mechanisms for nickel-induced oxidative DNA damage have been proposed as follows: all the nickel compounds used induced indirect damage through inflammation, and Ni3S2 also showed direct oxidative DNA damage through H2O2 formation. This double action may explain relatively high carcinogenic risk of Ni3S2. © 2001 Elsevier Science Inc.

DOI： 10.1016/S0891-5849(01)00558-5

Scopus

Oxidative DNA damage in cultured cells and rat lungs by carcinogenic nickel compounds 査読有り

S Kawanishi, S Inoue, S Oikawa, N Yamashita, S Toyokuni, M Kawanishi, K Nishino

FREE RADICAL BIOLOGY AND MEDICINE 31 巻 ( 1 ) 頁： 108 - 116 2001年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD

DNA damage in cultured cells and in lungs of rats induced by nickel compounds was investigated to clarify the mechanism of nickel carcinogenesis. DNA strand breaks in cultured cells exposed to nickel compounds were measured by using a pulsed held gel electrophoresis technique. Among nickel compounds (Ni3S2, NiO (black), NiO (green), and NiSO4), only Ni3S2, which is highly carcinogenic, induced lesions of both double- and single-stranded DNA in cultured human cells (Raji and HeLa cells). Treatment of cultured HeLa cells with Ni3S2 (10 mug/ml) induced a 1.5-fold increase in 8-hydroxy-2'-deoxyguanosine (8-OH-dG) compared with control, whereas NiO (black), NiO (green), and NiSO4 did not enhance the generation of 8-OH-dG. Intratracheal instillation of Ni3S2, NiO(black), and NiO(green) to Wistar rats increased 8-OH-dG in the lungs significantly. NiSO4 induced a smaller but significant increase in 8-OH-dG. Histological studies showed that all the nickel compounds used induced inflammation in lungs of the rats. Nitric oxide (NO) generation in phagocytic cells induced by Ni3S2, NiO(black). and NiO(green) was examined using macrophage cell line RAW 264.7 cells. NO generation in RAW 264.7 cells stimulated with lipopolysaccharide was enhanced by all nickel particles. Two mechanisms for nickel-induced oxidative DNA damage have been proposed as follows: all the nickel compounds used induced indirect damage through inflammation, and Ni3S2 also showed direct oxidative DNA damage through H2O2 formation. This double action may explain relatively high carcinogenic risk of Ni3S2. (C) 2001 Elsevier Science Inc.

DOI： 10.1016/S0891-5849(01)00558-5

Web of Science

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Endogenous formation of protein adducts with carcinogenic aldehydes - Implications for oxidative stress 査読有り国際誌

Ichihashi K, Osawa T, Toyokuni S, Uchida K

JOURNAL OF BIOLOGICAL CHEMISTRY 276 巻 ( 26 ) 頁： 23903 - 23913 2001年6月

Endogenous formation of protein adducts with carcinogenic aldehydes: Implications for oxidative stress Open Access

Ichihashi K., Osawa T., Toyokuni S., Uchida K.

Journal of Biological Chemistry 276 巻 ( 26 ) 頁： 23903 - 23913 2001年6月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Biological Chemistry

In the present study, we characterize the covalent modification of a protein by crotonaldehyde, a representative carcinogenic aldehyde, and describe the endogenous production of this aldehyde in vivo. The crotonaldehyde preferentially reacted with the lysine and histidine residues of bovine serum albumin and generated a protein-linked carbonyl derivative. Upon incubation with the histidine and lysine derivatives, crotonaldehyde predominantly generated β-substituted butanal adducts of histidine and lysine and N ε-(2,5-dimethyl-3-formyl-3,4-dehydropiperidino)lysine (dimethyl-FDP-lysine) as the putative carbonyl derivatives generated in the crotonaldehyde-modified protein. To verify the endogenous formation of crotonaldehyde in vivo, we raised the monoclonal antibody (mAb82D3) against the crotonaldehyde-modified protein and found that it cross-reacted with the protein-bound 2-alkenals, such as crotonaldehyde, 2-pentenal, and 2-hexenal. The anti-2-alkenal antibody recognized multiple crotonaldehyde-lysine adducts, including dimethyl-FDP-lysine and an unknown product, which showed the greatest immunoreactivity with the antibody. On the basis of the chemical and spectroscopic evidence, the major antigenic product was determined to be a novel Schiff base-derived crotonaldehyde-lysine adduct, Nε -(5-ethyl-2-methylpyridinium)lysine (EMP-lysine). It was found that the lysine residues that had disappeared in the protein treated with crotonaldehyde were partially recovered by EMP-lysine. The presence of immunoreactive materials with mAb82D3 in vivo was demonstrated in the kidney of rats exposed to the renal carcinogen, ferric nitrilotriacetate. In addition, the observations that the metal-catalyzed oxidation of polyunsaturated fatty acids in the presence of proteins resulted in an increase in the antigenicity of the protein indicated that lipid peroxidation represents a potential pathway for the formation of crotonaldehyde/2-alkenals in vivo. These data suggest that the formation of carcinogenic aldehydes during lipid peroxidation may be causally involved in the pathophysiological effects associated with oxidative stress.

DOI： 10.1074/jbc.M101947200

Open Access

Scopus

Difference in thioredoxin expression in viral myocarditis in inbred strains of mice Open Access

Miyamoto M, Kishimoto C, Shioji K, Nakamura H, Toyokuni S, Nakayama Y, Kita M, Yodoi J, Sasayama S

JAPANESE CIRCULATION JOURNAL-ENGLISH EDITION 65 巻 ( 6 ) 頁： 561 - 564 2001年6月

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